Discovery and Characterization of RGH-122, a Potent, Selective, and Orally Bioavailable V1a Receptor Antagonist.

The V1a receptor is a major contributor in mediating the social and emotional effects of arginine-vasopressin (AVP); therefore it represents a promising target in the treatment of several neuropsychiatric conditions. The aim of this research was to design and synthesize novel and selective V1a antagonists with improved and profiles. Through optimization and detailed SAR studies, we developed low nanomolar antagonists, and further characterizations led to the discovery of the clinical candidate compound (RGH-122).

Optimization of Novel α7 Nicotinic Acetylcholine Receptor Positive Allosteric Modulators and the Discovery of a Preclinical Development Candidate Molecule (RGH-560).

During optimization of a previously identified lead compound, attempts were made to optimize the reactive indole structural element, the suboptimal metabolic stability, as well as the low kinetic solubility. It was concluded that the indole was important for activity. With the aim of further improvements, more thorough modifications were also carried out.

Multiparameter Optimization of Naphthyridine Derivatives as Selective α5-GABA Receptor Negative Allosteric Modulators.

The discovery and characterization of novel naphthyridine derivatives with selective α5-GABAR negative allosteric modulator (NAM) activity are disclosed. Utilizing a scaffold-hopping strategy, fused [6 + 6] bicyclic scaffolds were designed and synthesized. Among these, 1,6-naphthyridinones were identified as potent and selective α5-GABAR NAMs with metabolic stability, cardiac safety, and beneficial intellectual property (IP) issues.

HTS-based discovery and optimization of novel positive allosteric modulators of the α7 nicotinic acetylcholine receptor.

HTS campaign of the corporate compound collection resulted in a novel, oxalic acid diamide scaffold of α7 nACh receptor positive allosteric modulators. During the hit expansion, several derivatives, such as 4, 11, 17 demonstrated not only high in vitro potency, but also in vivo efficacy in the mouse place recognition test. The advanced hit molecule 11 was further optimized by the elimination of the putatively mutagenic aromatic-amine building block that resulted in a novel, aminomethylindole compound family.

Discovery of novel positive allosteric modulators of the α7 nicotinic acetylcholine receptor: Scaffold hopping approach.

The paper focuses on the scaffold hopping-based discovery and characterization of novel nicotinic alpha 7 receptor positive modulator (α7 nAChR PAM) ligands around the reference molecule (A-867744). First, substantial efforts were carried out to assess the importance of the various pharmacophoric elements on the in vitro potency (SAR evaluation) by chemical modifications. Subsequently, several new derivatives with versatile, heteroaromatic central cores were synthesized and characterized.

Concerted action of antiepileptic and antidepressant agents to depress spinal neurotransmission: Possible use in the therapy of spasticity and chronic pain.

Chronic pain states and epilepsies are common therapeutic targets of voltage-gated sodium channel blockers. Inhibition of sodium channels results in central muscle relaxant activity as well. Selective serotonin reuptake inhibitors are also applied in the treatment of pain syndromes.

Tolperisone-type drugs inhibit spinal reflexes via blockade of voltage-gated sodium and calcium channels.

The spinal reflex depressant mechanism of tolperisone and some of its structural analogs with central muscle relaxant action was investigated. Tolperisone (50-400 microM), eperisone, lanperisone, inaperisone, and silperisone (25-200 microM) dose dependently depressed the ventral root potential of isolated hemisected spinal cord of 6-day-old rats. The local anesthetic lidocaine (100-800 microM) produced qualitatively similar depression of spinal functions in the hemicord preparation, whereas its blocking effect on afferent nerve conduction was clearly stronger.

Analysis of the effects of cannabinoids on synaptic transmission between basket and Purkinje cells in the cerebellar cortex of the rat.

The hypothesis of the present work was that activation of CB1 cannabinoid receptors inhibits GABAergic neurotransmission between basket and Purkinje cells in the cerebellar cortex. The aim was to test this hypothesis under near-physiological conditions. Action potentials of basket cells and spontaneous inhibitory postsynaptic currents (sIPSCs) in synaptically coupled Purkinje cells were recorded simultaneously in rat brain slices.

Inhibitory effect of anandamide on resiniferatoxin-induced sensory neuropeptide release in vivo and neuropathic hyperalgesia in the rat.

Anandamide (AEA) is an endogenous cannabinoid ligand acting predominantly on the cannabinoid 1 (CB(1)) receptor, but it is also an agonist on the capsaicin VR(1)/TRPV(1) receptor. In the present study we examined the effects of AEA and the naturally occurring cannabinoid 2 (CB(2)) receptor agonist palmitylethanolamide (PEA) on basal and resiniferatoxin (RTX)-induced release of calcitonin gene-related peptide (CGRP) and somatostatin in vivo. Since these sensory neuropeptides play important role in the development of neuropathic hyperalgesia, the effect of AEA and PEA was also examined on mechanonociceptive threshold changes after partial ligation of the sciatic nerve.

Concentration-dependent dual effect of anandamide on sensory neuropeptide release from isolated rat tracheae.

Most actions of anandamide (AEA) are mediated by the cannabinoid 1 (CB(1)) receptor activation, but on sensory neurones it is also an agonist on the vanilloid subtype 1 receptor (VR(1)). The aim of the present study was to analyse the effect of AEA (10(-6)-10(-4) M) on inhibitory CB(1) and excitatory VR(1) receptors by measuring sensory neuropeptide release such as somatostatin, substance P and calcitonin gene-related peptide, from isolated rat tracheae. AEA (10(-6) M) vas without significant effect, 10(-5) M inhibited neuropeptide release, which was abolished by the G protein-coupled receptor blocker pertussis toxin (100 ng/ml) and the CB(1) receptor antagonist SR141716A (5x10(-7) M).

Pharmacological characterisation of the somatostatin analogue TT-232: effects on neurogenic and non-neurogenic inflammation and neuropathic hyperalgesia.

The putative anti-inflammatory and anti-nociceptive activity of the heptapeptide somatostatin analogue TT-232 ( D-Phe-Cys-Tyr- D-Thr-Lys-Cys-Thr-NH(2)) was investigated in the rat and mouse, as well as its effect on neuropathic hyperalgesia, gastric ulceration and the release of sensory neuropeptides. In the rat, carrageenin-induced paw oedema was inhibited dose dependently by TT-232 (3x2.5-20 microg/kg i.

Analysis of the function of GABA(B) receptors on inhibitory afferent neurons of Purkinje cells in the cerebellar cortex of the rat.

Purkinje cells, the output neurons of the cerebellar cortex, receive inhibitory input from basket, stellate and neighbouring Purkinje cells. The aim of the present study was to clarify the role of GABAB receptors on neurons giving inhibitory input to Purkinje cells. In sagittal slices prepared from the cerebellar vermis of the rat, the GABAB receptor agonist baclofen lowered the frequency and amplitude of spontaneous inhibitory postsynaptic currents (IPSCs) recorded in Purkinje cells.

Interaction between interleukin 1beta and endogenous neurokinin 1 receptor agonists in mediating plasma extravasation and neutrophil accumulation in the cutaneous microvasculature of the rat.

Interleukin 1beta (IL-1beta) is a potent mediator of neutrophil accumulation. Antidromic stimulation of the rat saphenous nerve leads to neurogenic oedema formation mediated by endogenous tachykinins. Here, we have investigated links between IL-1beta and the tachykinin 1 (NK(1)) receptors in microvascular events in rat skin.